Four million Americans currently suffer from Alzheimer's disease (AD), and experts estimate that 22 million people around the world will be so afflicted by 2025. Acetylcholinestase inhibitors dominate the current AD market driving its value to over US$1.2 billion in 2001. Although current AD treatments center on treating symptoms, future strategies are more likely to modify the course of the disease. The most widely accepted hypothesis on the etiopathogenesis of AD proposes that aggregates of the amyloid protein, trigger tau hyperphosphorylation and neural degeneration. Neurotoxicity is thought to be due to altered calcium regulation, mitochondrial damage and/or immune stimulation. Our January 10th edition of TherapeuticAdvances featured progress in vaccine therapy designed to limit amyloid accumulation. On the other hand, as discussed in our recent DiscoveryDossier, the use of glycogen synthase kinase (GSK)-3 inhibitors is rapidly emerging as a highly promising small molecule approach to AD as well as a host of other serious conditions. GSK-3 is elevated in AD brain, phosphorylating tau and also possibly providing a common docking site for tau and presenelin-1, a third protein associated with AD. GSK-3 inhibitors prevent tau hyperphosphorylation, reduce the release of Aß from transfected COS7 cells and also protect cultured neurons from cell death triggered by Aß.

Spanish researchers have recently characterized transgenic mice that conditionally over-express GSK-3beta in hippocampal and cortical neurons. These mice, designated Tet/GSK-3beta, show many of the biochemical and cellular aspects of AD neuropathology such as tau hyperphosphorylation and somatodendritic localization, decreased nuclear beta-catenin, neuronal death and reactive gliosis. More recently this group reports spatial learning deficits of Tet/GSK-3beta mice in the Morris water maze, mirroring the cognitive disorder hallmarking AD. These data demonstrate that GSK-3 deregulation contributes not only to biochemical and cellular events characteristic of AD, but that this enzyme contributes to neurological deficits associated with AD pathogenesis. It is therefore proposed that the Tet/GSK-3beta mouse should be used as an AD model and that this strain can be used to test the therapeutic potential of the selective GSK-3 inhibitors that are currently under development 

Entry date January, 2003

Adapted from Hernandez et al, - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.